Bladder cancer is the 6th most common cancer in the United States; it is the 3rd most common cancer in men and the 11th most common in women. Approximately 75% of bladder cancers are of the non-muscle invasive type (Babjuk et al., 2013). Non-muscle invasive bladder cancers (NMIBCs) are categorized as Ta (non-invasive papillary carcinoma), T1 (tumor invades lamina propria or subepithelial connective tissue), and Tis (carcinoma in situ). Ta tumors are the most common, representing about 70% of NMIBCs, but only about 7% of these are categorized as high-grade (Sylvester et al., 2005). About 20% of NMIBCs are T1 tumors (Anastasiadis et al., 2012) T1 tumors are more aggressive than Ta tumors, and considered high-risk (Babjuk et al., 2013; American Urological Association, 2014) Flat, high-grade tumors confined to the mucosa (non-invasive) are characterized as carcinoma in situ (CIS), ((Babjuk et al., 2013) and these represent approximately 10% of the NMIBCs (Anastasiadis et al., 2012).
The usual first treatment for NMIBC (high grade Ta, T1, and CIS) is transurethral resection of the bladder tumors (TURBT), followed by intravesical immunotherapy, most commonly with bacillus Calmette-Guérin (BCG) (Babjuk et al., 2013, American Urological Association 2014), In patients with T1 tumors, a second TURBT is recommended (Babjuk et al., 2013, American Urological Association 2014). Local and systemic side effects are common with intravesical BCG therapy, causing discontinuation of treatment in approximately 20% of patients (Sylvester et al., 2011). Approximately 75% of patients experience local side effects (including cystitis, irritative voiding symptoms, and hematuria), while 40% report systemic side effects, including general malaise and fever (Sylvester et al., 2011). Intravesical BCG failure occurs in up to 40% of patients (Sylvester et al., 2011). Because of the high risk for development of muscle invasive disease, cystectomy is recommended for CIS and high-grade Ta and T1 patients who experience disease recurrence following intravesical therapy. For patients unable or unwilling to undergo cystectomy, treatment options are limited. Thus, there is a need in the art for safe and effective therapies and optimal dosing regimens of safe and effective therapies for bladder cancer.